Preparationof enantiomerically pure 3-protected amino-pyrrolidines

ABSTRACT

A process for the preparation of enantiomerically homogeneous aminopyrrolidinyl naphthyridine carboxylic acids and quinolone carboxylic acids, and for the preparation of intermediates that are useful in the production of these carboxylic acids.

This is a division of application Ser. No. 167,058, filed Mar. 11, 1988,now U.S. Pat. No. 4,859,776.

TECHNICAL FIELD

This invention relates to a new process for the preparation ofenantiomerically homogeneous aminopyrrolidinyl naphthyridine carboxylicacids and quinolone carboxylic acids, particularly to(S)-7-(3-aminopyrrolidin1-yl)-1-(o,p-difluorophenyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylicacid, to the preparation of intermediates that are useful in thepreparation of these carboxylic acids, as well as to a novel azidereduction process for the reductive acetylation of an azido substituent.

BACKGROUND ART

Two molecules that possess identical chemical formulas with the sameatoms bonded one to another but that differ in the manner that thoseatoms are arranged in space are referred to as stereoisomers.Stereoisomers that are mirror images of each other such that they arenot superimposable one upon the other, because they have oppositeconfigurations, are referred to as enantiomers. A mixture of equal partsof the two mirror image forms, or enantiomeric forms, is referred to asa racemic mixture.

Physiological activity has been shown to be closely related to theconfiguration of a molecule. For example, it is known that oneenantiomeric form of adrenalin is over ten times more active in raisingblood pressure than is the other form. Additionally, enzymes whichcatalyze chemical reactions in the body are frequently programmed toaccept one enantiomeric form but not the other.

7-(Aminopyrrolidin-1-yl)naphthyridine carboxylic acids (Chu, U.S. Pat.No. 4,616,019, issued Oct. 7, 1986) and7-(aminopyrrolidin-1-yl)quinolone carboxylic acids (Chu, U.S. Pat. No.4,730,000, issued Mar. 8, 1988) are known to be antibacterial agents. Aracemic mixture of 7-(3aminopyrrolidin-1-yl)-1-(o,p-difluorophenyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylicacid has been shown to exhibit antibacterial properties. J. Med. Chem.,29, 2363 (1986).

A racemic mixture of 7-(3-aminopyrrolidin 1-yl)-1-(o,pdifluorophenyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylicacid is prepared by Reaction Scheme I as illustrated below: ##STR1##

In Reaction Scheme I, the oxime (2) is reduced with Raney nickel andhydrogen which results in a racemic mixture having equal parts of thetwo enantiomeric forms of the molecule (3). This racemic intermediatewill subsequently result in the production of a racemic mixture of (A).However, only one enantiomeric form of (A) may possess biologicalactivity. Further, one enantiomeric form of this molecule may be capableof producing an undesirable side effect while the other enantiomericform may be the form that exhibits antibacterial properties. It istherefore desirable to provide a process for the preparation of aspecific enantiomeric form of7-(3-aminopyrrolidin-1-yl)-1-(o,p-difluorophenyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylicacid.

As will be discussed in greater detail below, one alternative is toprovide an azide rather than the oxime (2), reduce the azide to anamine, acetylate the amine, and thereafter remove the benzyl group toobtain (4). The reduction of an azide to an amine is a process that iswidely used in organic synthesis because of the high stereoselectivityassociated with the preparation of the precursor azide. Accordingly,several methods and reagents are known to reduce an azide to an amine.For example, catalytic hydrogenation [Mungall, J. Org. Chem., 40, 1659(1975); and Corey, Synthesis, 590 (1975)], or lithium aluminum hydride[Hedayatullah, Tetrahedron Lett., 2455 (1975); Brimacombe, Carbohydr.Res., 3, 318 (1967); Bose, J. Org. Chem., 27, 2925 (1962); and Boyer, J.Am. Chem., 73, 5865 (1951)]. Other processes include H₂ S/pyridine/H₂ O[Adachi, Synthesis, 45 (1977)]; transfer hydrogenation [Gartiser,Tetrahedron Lett., 24, 1609 (1984)]; Ph₃ P/NH₄ OH [Vaulter, TetrahedronLett., 24. 763 (1983)]; H₂ /Lindlar catalyst [Corey, Synthesis, 590(1975); Cr(II)/H+[Kirk, J. Chem. Soc. Chem. Commun., 64 (1970); andKondo, Tetrahedron, 29, 1801 (1973)]; as well as Na₂ S/Et₃ N/MeOH[Belinka, J. Org. Chem., 44, 4712 (1979)]. Most recently, there havebeen reports of procedures using stannous chloride/MeOH [Maiti,Tetrahedron Lett., 27, 1423 (1986)]and NaBH₄ /THF/MeOH [Soai, Synthesis,48 (1986)]. Although many reagents have been proposed, none have provencompletely satisfactory because they either lack chemoselectivity orrequire vigorous reaction conditions to achieve the desired reduction ofthe azide.

DISCLOSURE OF THE INVENTION

It has now been discovered that(S)-7-(3-aminopyrrolidin-1-yl)-1-(o,p-difluorophenyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylicacid can be prepared according to Reaction Scheme II, illustrated below:##STR2## wherein R₁ is an N-1 protecting group such as benzyl,carbobenzyloxy, tert-butoxycarbonyl, C₁ to C₆ alkanoyl, aroyl, or alkyl-or arylsulfonyl; R₂ is an activating group such as methanesulfonyl,p-toluenesulfonyl, or trifluoromethanesulfonyl, which transform thehydroxyl group into a leaving group; R₃ is amino or a functional groupwhich may be converted to an amine stereospecifically with retention ofconfiguration, such as azido or nitro; and R₄ is a nitrogen protectinggroup that is selected to be stable under the conditions required toremove the nitrogen protecting group R₁. Therefore, R₄ can includebenzyl, carbobenzyloxy, tert-butoxycarbonyl, C1 to C₆ alkanoyl, aroyl,or C₁ to C₆ alkyl- or arylsulfonyl, and in some cases arylmethyl, acetylor hydrogen depending on the substituent employed for R₁. Preferably, R₁is benzyl, R₂ is methanesulfonyl, R₃ is azide and R₄ is acetyl. Where R₃is an azide, reductive acetylation of the azide (10) is preferablyachieved with thiolacetic acid to form the corresponding acetamide (11)in a single step.

The term "C₁ to C₆ alkyl" as used herein refers to straight or branchedchain alkyl radicals containing from 1 to 6 carbon atoms.

The term "C₁ to C₆ alkanoyl" as used herein refers to R₅ CO--wherein R₅is C₁ to C₆ alkyl.

The term "aroyl" as used herein refers to R₆ CO--wherein R₆ is phenyl orsubstituted phenyl wherein the phenyl ring is substituted with one, twoor three substituents independently selected from halogen, loweralkyl,nitro and alkoxy.

The term "halogen" as used herein refers to fluoro, bromo, chloro oriodo.

The term "C₁ to C₆ alkylsulfonyl" as used herein refers to R₇ SO₂--wherein R₇ is C₁ to C₆ alkyl.

The term "arylsulfonyl" as used herein refers to R₈ SO₂ -- wherein R₈ isphenyl or p-tolyl.

The term "alkoxy" as used herein refers to R₉ O-- wherein R₉ is aloweralkyl radical.

The term "leaving group" as used herein refers to chloro, bromo, iodo,or sulfonate esters such as mesylate, triflate, tosylate and the like.

The term "N-1 protecting group" or "nitrogen protecting group" as usedherein refers to those groups intended to protect an amino group againstundesirable reactions during synthetic procedures and includes but isnot limited to benzyl, acetyl, pivaloyl, tert-butoxycarbonyl,carbobenzyloxy or benzoyl.

As used herein, the term "pharmaceutically acceptable salts" means thenontoxic acid addition or alkaline earth metal salts of the compound offormula (A). These salts can be prepared in situ during the finalisolation and purification of the compound of formula (A), or byseparately reacting the base or acid functions with a suitable organicor inorganic acid or base, respectively. Representative acid additionsalts include the hydrochloride, hydrobromide, sulfate, bisulfate,acetate, oxalate, valerate, oleate, palmitate, stearate, laurate,borate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, napsylate, glucoheptonate, lactobionate,lauryl sulfate salts and the like. Representative alkali metal oralkaline earth metal salts include the sodium, calcium, potassium andmagnesium salts, and the like.

In accordance with the foregoing Reaction Scheme II, an N-1 protected(R)-3-hydroxypyrrolidine intermediate (R)-(8) is utilized to prepare theenantiomerically homogeneous(S)-7-(3-aminopyrrolidin-1-yl)-1-(o,p-difluorophenyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylicacid (A). For example, the enantiomerically homogeneous alcohol (R)-(8),where the N-1 protecting group R₁ is benzyl, is reacted with asulfonating reagent such as an alkyl- or arylsulfonyl chloride or analkyl- or arylsulfonic acid anhydride to obtain a sulfonate ester (9).The reaction takes place in an organic solvent such as dimethylformamide(DMF), dichloromethane, tetrahydrofuran (THF), or pyridine in thepresence of a base such as triethylamine or1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The temperature range isapproximately -30 to 60 degrees Celsius (C.). Preferably, (R)-(8), isreacted with methanesulfonyl chloride in dichloromethane and in thepresence of the base triethylamine to obtain the sulfonate ester (9),where R₂ is methanesulfonyl. This reaction proceeds acceptably at roomtemperature but is preferably run at approximately 25 degrees C.

The sulfonate ester group is displaced with a nitrogen nucleophile, suchas an ammonia, phthalimide or an azide reagent to obtain (10). Azidereagents can include, among others, sodium azide, lithium azide, ortetra n-butylammonium azide in an organic solvent, such as acetonitrile,DMF, or THF. The reaction can take place within a temperature range offrom approximately room temperature to 125 degrees C. Preferably, thesulfonate ester (9) is reacted with tetra-n butylammonium azide inacetonitrile to provide the azide (10).

The nitrogen nucleophile is then transformed to provide an amine (11).Where the nitrogen nucleophile is an azide, the transformation can beaccomplished with hydrogen and a metallic catalyst such as platinum oncarbon (Pt/C) or palladium on carbon (Pd/C) in an organic solvent, suchas methanol or ethanol to provide the amine (11). On the other hand, ahydride reagent, such as lithium aluminum hydride or lithium borohydridecan be used to reduce the azide group. The resulting amine (11) is thenacylated with a carboxylic acid anhydride, preferably acetic anhydride,and the R₁ group is cleaved to obtain (12), where R₄ is acetyl.

The acylated compound (12) is subsequently reacted to form (A) in aprocess similar to that found in the reaction illustrated in ReactionScheme I. In other words, the compound (12), in this case(S)-3-acetamidopyrrolidine, is reacted with7-chloro-1-(o,p-difluorophenyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylicacid or its ethyl ester (5) to obtain (13) after which the ester andamide groups are hydrolyzed to obtain(S)-7-(3-aminopyrrolidin-1-yl)-1-(o,p-difluorophenyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylicacid (A).

Alternatively, the azide (10) can be directly converted to an acetamide(11). It has now been discovered that azides will react with thiolaceticacid to provide chemoselective reduction of the azide with anaccompanying acetylation to give the corresponding acetamide. Thereductive acetylation of azides with thiolacetic acid has been found tohave general utility for the reduction of functionally diverse azides.Further, the reaction occurs in the presence of a wide variety offunctional groups, such as t-butoxycarbonyl and benzyl protectinggroups, methyl esters, olefins, carboxylic esters, and methanesulfonateester.

The reaction is rapid and generally occurs under mild conditions. Forexample, the reaction takes place at room temperature, with or without asolvent, to reach completion within a matter of minutes. Further, thereaction is extremely convenient to carry out and is accomplished bysimply stirring the azide with thiolacetic acid. Thereafter, thereaction mixture can be concentrated with a rotary evaporator and, ifdesired, further purified by flash column chromatography.

Additionally, the reductive acetylation of azides with thiolacetic acidis advantageous with molecules that possess functional groups that werepreviously thought to be incompatible with a free amine. As seen inReaction Scheme III below, treatment of the azido mesylate (14) withhydrogen and metal catalyst such as palladium in the presence ofmethanol, results in the reduction of the azide and subsequentintramolecular cyclization to yield the bicyclic amine (15). Thiscyclization occurs spontaneously and no amino mesylate is obtained.However, treatment of (14) with thiolacetic acid results in theacetamido mesylate (16). It is believed that the acetylation occurs sorapidly that the amine is trapped before intramolecular displacement canoccur. ##STR3##

As illustrated in Reaction Scheme IV below, the starting material (11)can be prepared by hydroborating N-benzyl-3-pyrroline (17) withdiisocamphenylborane to form an organoborane complex. Brown, J. Org.Chem., 51, 4296-4298 (1986). In this case, the organoborane complex isthen reacted with NH₂ Cl (Brown, J. Am. Chem. Soc., 86, 3565 (1964)) toprovide (18) in optically active form. The product (18) is thereaftertreated, as discussed above, to form the starting material (11) (R₄ =Ac)##STR4##

The differences in in vivo antibacterial activity of racemic (R,S)compound (A) versus the (S) enantiomeric form of compound (A) are shownin Table I.

                  TABLE I                                                         ______________________________________                                        POTENCY OF (A) IN MOUSE PROTECTION TESTS                                                         ED.sub.50 (mg/kg/day)                                      Organism   Compound      Subcutaneous                                                                             Oral                                      ______________________________________                                        E. Coli Juhl                                                                             (R,S)-(A)     0.3        1.2                                                  (S)-(A)       0.2        0.8                                       P. Aeruginosa                                                                            (R,S)-(A)     >20        16.0                                      5007       (S)-(A)       8.6        12.1                                      S. Aureus  (R,S)-(A)     0.4        1.0                                       NCTC 10649 (S)-(A)       0.4        0.8                                       ______________________________________                                    

The foregoing may be better understood from the following examples,which are presented for the purposes of illustration and are notintended to limit the scope of the inventive concepts. As used in thefollowing examples, the references to compounds, such as (1), (2), (3),etc. and to substituents, such as R, R₁, R₂, etc., refer to thecorresponding compounds and substituents in the foregoing reactionschemes.

EXAMPLE 1 (3S) 3-Acetamidopyrrolidine (12)

(a) Under a nitrogen atmosphere, 3.8 mL (6.1 g, 60.8 mmol) ofmethanesulfonyl chloride was slowly added to a solution of 4.3 g (24.3mmol) of an N-1 protected (R)-(8) (J. Org. Chem. 51 4298 (1986)), whereR₁ is benzyl, 8 mL of dichloromethane, and 8.5 mL (6.1 g, 60.8 mmol) oftriethylamine. The solution was stirred at room temperature forapproximately 16 hours after which the reaction mixture was diluted withdichloromethane and washed with saturated aqueous sodium bicarbonate andbrine. The dichloromethane solution was dried (sodium sulfate) andconcentrated with a rotary evaporator. The crude product was thenpurified by flash column chromatography utilizing 4:1 ethylacetate/hexanes as eluant to obtain 3.3 g of the sulfonate ester (9),where R₁ is benzyl and R₂ is SO₂ CH₃, as a yellow oil. ¹ H NMR (CDCL₃)2.10 (m, 1H), 2.30 (m, 1H), 2.50 (m, 1H), 2.75-2.90 (comples m, 3H),3.00 (s, 3H), 3.62 (d, 1H, J=12.6 Hz), 3.68 (d, 1H, J=13.5 Hz), 5.20 (m,1H), 7.30 (m, 5H).

(b) Under a nitrogen atmosphere, 7.5 g (26.4 mmol) oftetra-N-butylammonium azide was added to a solution of 3.2 g (12.5 mmol)of the sulfonate ester (9) and 4 mL of acetonitrile. The solution washeated at approximately 65 degrees C. for 3 hours. The reaction mixturewas then diluted with ether, washed with saturated aqueous sodiumbicarbonate, dried, and concentrated with a rotary evaporator. The crudematerial was purified by flash column chromatography as above to obtain2.29 g of (10), where R₁ is benzyl and R₃ is azido, as a colorless oil.¹ H NMR (CDCl₃): 1.90 (m, 1H), 2.20 (m, 1H), 2.46 (m, 1H), 2.70 (complexm, 3H), 3.60 (d, 1H, J=12 Hz), 3.68 (d, 1H, J=13.5 Hz), 3.95 (m, 1H),7.35 (m, 5H).

(c) Under a nitrogen atmosphere, a solution of 216 mg (1.07 mmol) of theazide (10), and 0.85 mL (0.9 g, 11 mmol) of thiolacetic acid was stirredat room temperature for approximately 5 hours and concentrated with arotary evaporator. The crude material was subjected to flash columnchromatography, increasing the polarity of the eluant from chloroform to1:9 methanol/chloroform, to obtain (11), where R₄ is acetyl and R₁ isbenzyl, as an oil. ¹ H NMR (CDCl₃): 1.60 (m, 1H), 1.94 (s, 3H), 2.25 (m,2H), 2.53 (dd, 1H, J=6, 10.5 Hz), 2.61 (dd, 1H, J=3, 10.5 Hz), 2.85 (m,1H), 3.59 (s, 2H), 4.45 (m, 1H), 5.95 (bd, NH, J=6 Hz), 7.30 (m, 5H).The oil was dissolved in methanol and 50 mg of 20% Pd/C was added to thesolution. The mixture was then placed under 4 atm of hydrogen for 24hours. An additional 0.46 g 20% Pd/c was added to the system during thistime. The catalyst was filtered out and the solvent was removed with arotary evaporator to yield 130 mg of (12), where R₄ is acetyl, as ayellow oil. ¹ H NMR (CDCl₃) 1.67 (m, 1H), 1.97 (s, 3H), 2.16 (m, 1H),2.85 (dd, 1H, J=3, 11 Hz), 2.96 (m, 1H), 3.11 (m, 2H), 3.48 (s, 1H),4.41 (m, 1H), 6.26 (bs, 1H).

An alternate preparation of (3S)-3-acetamidopyrrolidine (12) began byrepeating steps (a) and (b) as described above. However, instead ofreducing the product (10) with thiolacetic acid, the reduction wasaccomplished with hydrogen in the presence of a platinum catalyst toobtain the amine (11). The amine was thereafter acylated with aceticanhydride and the R₁ group was cleaved as described above to obtain(12), where R₄ is acetyl.

A second alternate preparation of (3S)-3-acetamidopyrrolidine (12)involves repeating steps (a)-(c) described above, but replacing benzylas the N-1 protecting group R₁ with a tert-butoxycarbonyl N-1 protectinggroup. The tert-butoxycarbonyl protecting group is removed under acidicconditions to obtain (12), where R₄ is acetyl.

EXAMPLE 2 (S)-7(3-Aminopyrrolidin-1-yl)-1-(o,p-difluorophenyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylicAcid (A) Hydrochloride

(a) Under a nitrogen atmosphere, 430 mg (1.13 mmol) of (5) was added toa solution of 120 mg (0.94 mmol) of the product (12) from Example 1, 0.3mL of pyridine, and 0.17 mL (120 mg, 1.2 mmol) of triethylamine. J. Med.Chem., 29, 2363 (1986). The solution was heated at approximately 65degrees C. for 21 hours to allow the reaction to come to completionbefore concentrating with a rotary evaporator. The crude material waspurified by subjecting the product to flash column chromatography,gradually increasing the polarity of the eluant from chloroform to 5%methanol/chloroform, to obtain 343 mg of (13) as an orange solid (mp240-243 degrees C.).

(b) Under a nitrogen atmosphere, 9.5 mL of a 1M aqueous sodium hydroxidesolution was added to a suspension of 223 mg (2.48 mmol) of the product(13) from step (a) and 3 mL of THF. The reaction mixture was heated atapproximately 65 degrees C. for 2 hours before being concentrated with arotary evaporator.

(c) The residue from step (b) was suspended in 6 M aqueous hydrochloricacid and heated to reflux (110 degrees C.). The mixture was then cooledand concentrated. Thereafter, H₂ O was added to the concentrated mixtureresulting in an off-white solid (A) hydrochloride which was collectedand dried in a vacuum oven yielding 101 mg of product. 1 H NMR (dmso-d₆)2-3.9 (complex), 7.38 (m,1H), 7.57 (m,1H), 7.83 (m,1H), 8.23(d,1H,J=14), 8.83 (s,1H).

EXAMPLE 3 [(S)-(1-Methoxy-1-phenyl 1-trifluoromethyl)methyl]Amide of(S)3-Amino-1-benzylpyrrolidine

(a) To a solution of 35 mg (0.17 mmol) of the product 10, where R₁ isbenzyl and R₃ is azido, in 15 mL of methanol was added 18 mg of 5% Pt/Cand the mixture was placed under 4 atm of hydrogen. The catalyst wasremoved by filtration and the filtrate was concentrated with a rotaryevaporator to obtain a yellow oil.

(b) To a solution of the oil from step (a) and 0.05 mL of pyridine wasadded 0.05 mL (35 mg, 0.35 mmol) of triethylamine and 0.05 mL (68 mg,0.27 mmol) of (S)-(1-Methoxy-1-phenyl-1-trifluoromethyl)methyl acylchloride. The reaction mixture was stirred under nitrogen at roomtemperature for approximately 8 hours, diluted with ether, and washedwith saturated aqueous sodium bicarbonate and brine. The ether solutionwas then dried and concentrated with a rotary evaporator before beingpurified by flash column chromatography to obtain the[(S)-(1-Methoxy-1-phenyl-1-trifluoromethyl)methyl]Amide of(S)-3-Amino-1-benzylpyrrolidine as a yellow oil. ¹⁹ F NMR 8.236 ppm(internal standard trifluoroethanol). This NMR data indicates that the(S) 3-amino-benzylpyrrolidine obtained in step (a) is enantiomericallypure.

EXAMPLE 4 [(S)-(1-Methoxy 1-phenyl-1-trifluoromethyl)methyl]Amide of(R)3-Amino-1-benzylpyrrolidine

The corresponding amide of (R)-3-amino 1-benzyl pyrrolidine can beprepared according to Example 3 by simply substituting one enantiomericform of the starting material (10) with the opposite enantiomeric form.

EXAMPLE 5 (2S,4S)-4-Acetamido-1-t-butoxycarbonyl-2-methylpyrrolidine

Under a nitrogen atmosphere, 0.27 mL (280 mg, 3.7 mmol) of thiolaceticacid was added to 210 mg (0.93 mmol) of(2S,4S)-4-azido-1-t-butoxycarbonyl-2-methylpyrrolidine. The reactionmixture was stirred at room temperature for approximately four hours andconcentrated with a rotary evaporator. The resulting oil was subjectedto flash column chromatography using 1:1 ethyl acetate/hexane followedby ethyl acetate as eluant to obtain 190 mg of(2S,4S)-4-acetamido-1-t-butoxycarbonyl-2-methylpyrrolidine (84% yield)as a yellow oil which solidified on standing. Recrystallization of asmall sample from hexanes provided a white solid, mp 108-110 degrees C.The material thus obtained was found to be identical to the materialobtained by a two-step procedure that provides for the hydrogenation of(2S,4S)-4-azido-1-t-butoxycarbonyl-2-methylpyrrolidine with hydrogen andPd/C followed by a separate acetylation step utilizing acetic anhydride.

EXAMPLE 6 Benzylacetamide

Under a nitrogen atmosphere, 1.2 mL (1.3 g, 17.2 mmol) of thiolaceticacid was added to 570 mg (4.3 mmol) of benzyl azide. The reactionmixture was stirred at room temperature for approximately one hour andthe thioacetic acid was removed with a rotary evaporator. The resultingoil was subjected to flash column chromatography using 1:1 ether/pentanefollowed by ether as eluant to obtain 580 mg of benzylacetamide (91%yield) as a white crystalline solid, mp 58-60 degrees C.

Alternatively, benzylacetamide was prepared according to the followingprocedure. Under a nitrogen atmosphere, 1.4 mL (1.5 g, 20 mmol) ofthiolacetic acid was added to 0.54 mL (535 mg, 5 mmol) of benzylamine. Aprecipitate formed immediately. The thiolacetic acid was removed with arotary evaporator to obtain 740 mg of benzylacetamide as a yellow solid.Recrystallization of the product from hexanes provided 690 mg (92%yield) of benzylacetamide. The physical and spectral properties of thematerial thus obtained were identical with those of the product obtainedupon treatment of benzyl azide with thiolacetic acid as described inExample 7. The physical and spectral properties of the material obtainedin this manner were identical with those of the product obtained upontreatment of benzylazide with thiolacetic acid.

EXAMPLE 7

In the fashion described in Examples 6 through 8, and corresponding tothe transformation of (10) wherein R₃ is azide into (11) wherein R₄ isacetyl, the azide compounds listed in Table II were reacted with four toten mole equivalents of thiolacetic acid. The resulting acetamide wasconcentrated with a rotary evaporator before being purified by flashcolumn chromatography.

                  TABLE II                                                        ______________________________________                                                               % Yield of                                             Azide                  Acetamide mp                                           ______________________________________                                        (1)                                                                                  ##STR5##        77        oil                                          (2)                                                                                  ##STR6##        92        62-64 degrees C.                             (3)   CH.sub.3 (CH.sub.2).sub.6 N.sub.3                                                              77        oil                                          (4)                                                                                  ##STR7##        65        104 degrees C.                               (5)                                                                                  ##STR8##        73        88-90 degrees C.                             (6)                                                                                  ##STR9##        70        oil                                          ______________________________________                                    

It will be understood that various changes and modifications can be madein the details of the procedure to adapt it to various conditionswithout departing from the spirit of the invention, especially asdefined in the following claims.

What is claimed is:
 1. A process for the preparation of theenantiomerically pure (S) form of a compound having the formula:##STR10## wherein R₄ is a nitrogen protecting group, the processcomprising: (a) transforming the hydroxyl group of a N-1 protectedenantiomerically pure (R)-3-hydroxypyrrolidine into a leaving group;(b)introducing a nitrogen containing substituent by displacing the leavinggroup with a nitrogen nucleophile that is a precursor to an amino; (c)converting the nitrogen nucleophile to an amine, which is then protectedwith a nitrogen protecting group R₄ that is stable under the conditionsrequired to cleave the N-1 protecting group; and (d) cleaving the N-1protecting group.
 2. The process as defined in claim 1 wherein the N-1protecting group is selected from the group consisting of benzyl,carbobenzyloxy, tert-butoxycarbonyl, C₁ to C₆ alkanoyl, aroyl, and C₁ toC₆ alkylsulfonyl or arylsulfonyl; and R₄ is selected from the groupconsisting of C₁ to C₆ alkanoyl, tert-butoxycarbonyl, carbobenzyloxy, C₁to C₆ alkylsulfonyl or arylsulfonyl, aroyl and arylmethyl.
 3. Theprocess as defined in claim 1 wherein the leaving group is chloro,bromo, iodo or a sulfonate ester.
 4. The process as defined in claim 1wherein the nitrogen nucleophile is an azide, phthalimide, nitro orammonia reagent.
 5. The process as defined in claim 4 wherein the azidereagent is selected from the group consisting of sodium azide, lithiumazide, and tetra n-butylammonium azide.
 6. The process as defined inclaim 4 wherein the azide substituent is reductively acetylated withthiolacetic acid to form an acetamide, with retention of configuration,in a single step.
 7. A process for the preparation of enantiomericallypure (S)-3-acetamidopyrrolidine, the process comprising:(a) reacting anenantiomerically pure N-1 protected (R) 3-hydroxypyrrolidine withmethanesulfonyl chloride to convert the hydroxyl group of the N-1protected (R)-3-hydroxypyrrolidine to a sulfonate ester; (b) reactingthe sulfonate ester with tetra-n-butylammonium azide to obtain thecorresponding azide; (c) reducing the azide to form an amine; (d)acetylating the amine to form an acetamide; and (e) cleaving the N-1protecting group to obtain enantiomerically pure(S)-3-acetamidopyrrolidine.
 8. The process as defined in claim 7comprising reductively acetylating the azide formed in step (b) withthiolacetic acid to form the corresponding acetamide in a single step.9. The process as defined in claim 7 wherein the N-1 protecting group isselected from the group consisting of benzyl, carbobenzyloxy,tert-butyloxycarbonyl, C₁ to C₆ alkanoyl, aroyl, and C₁ to C₆alkylsulfonyl or arylsulfonyl.